Atherosclerosis Atheroma are not merely filled with lipid

Atherosclerosis

Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall Cells: n Endothelium n Smooth Muscle Cells Inflammatory Cells: n Macrophages n T Lymphocytes n Mast Cells

Cell Types in the Human Atheroma Monocyte/ Macrophage Intima Tunica Media Endothelium T-lymphocytes Smooth muscle cells

Schematic Time Course of Human Atherogenesis Ischemic Heart Disease Cerebrovascular Disease Peripheral Vascular Disease Lesion initiation No symptoms + Symptoms Time (y) Symptoms

Macrophage Functions in Atherogenesis Attachment

Leukocyte–Endothelial Adhesion Molecules Mono T B PMN

Vascular Cell Adhesion Molecule 1 (VCAM-1) n Binds monocytes and lymphocytes - Cells found in atheroma n Expressed by endothelium over nascent fatty streaks n Expressed by microvessels of the mature atheroma

An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium Li H et al. Arterioscler Thromb 1993; 13: 197 -204.

VCAM-1 Expression in Rabbit Aorta 3 weeks on atherogenic diet Li H et al. Arterioscler Thromb 1993; 13: 197 -204.

Macrophage Functions in Atherogenesis Penetration

Monocyte Chemoattractant Protein 1 (MCP-1) n A potent mononuclear cell chemoattractant n Produced by endothelial and smooth muscle cells n Localizes in human and experimental atheroma

Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low -density lipoprotein receptor–deficient mice Gu L et al. Mol Cell 1998; 2: 275 -281.

Reduced Lipid Deposition in MCP-1– Deficient Atherosclerotic Mice LDL-R –/– MCP-1 +/+ LDL-R –/– MCP-1 –/– Gu L et al. Mol Cell 1998; 2: 275 -281.

% Aortic Surface Stained Oil Red Staining Reduced Lipid Deposition in MCP-1– Deficient Atherosclerotic Mice Time on Diet: ** * +/+ -/12 – 14 weeks Gu L et al. Mol Cell 1998; 2: 275 -281. +/+ -/20 – 25 weeks *P = 0. 001 compared to +/+ **p = 0. 005 compared to +/+

Macrophage Functions in Atherogenesis Activation

Macrophage Functions in Atherogenesis Division

Macrophage Colony-Stimulating Factor (M-CSF) n A potent monocyte activator and co-mitogen n Produced by endothelial and smooth muscle cells n Localizes in human and experimental atheroma

Augmented M-CSF gene expression in human and experimental atherogenesis Rosenfeld ME et al. Am J Pathol 1992; 140: 291 -300. Clinton SK et al. Am J Pathol 1992; 140: 301 -316.

M-CSF Expression in Atheroma Intimal M-CSF in Atheroma

M-CSF Promotes Atherogenesis Smith JD et al. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A 1995; 92: 8264 -8268. Qiao JH et al. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol 1997; 150: 1687 -1699. Rajavashisth T et al. Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor– deficient mice. J Clin Invest 1998; 101: 2702 -2710.

M-CSF Deficiency (op mutation) Reduces Atheroma in LDL Receptor–Knockout Mice +/+ op/+ Rajavashisth T et al. J Clin Invest 1998; 101: 2702 -2710. op/op

Fatty Lesions in Aortic Root ( m 2/section) M-CSF Gene Dosage Relates to Atheroma Size in LDLR –/– Mice 107 (12) 106 105 (10) * 104 (4) * 103 +/+ op/op Genotype Rajavashisth T et al. J Clin Invest 1998; 101: 2702 -2710.

Molecular Mediators of Atherogenesis VCAM-1 MCP-1 M-CSF

Anatomy of the Atherosclerotic Plaque Fibrous cap Lumen Lipid Core Shoulder Intima Media Elastic laminæ Internal External

Schematic Time Course of Human Atherogenesis Ischemic Heart Disease Cerebrovascular Disease Peripheral Vascular Disease Transition from chronic to acute atheroma

Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Syndromes, Results from: n Weakening of the fibrous cap n Thrombogenicity of the lipid core Illustration courtesy of Michael J. Davies, M. D.

Matrix Metabolism and Integrity of the Plaque’s Fibrous Cap Brea is s e h t Syn IFN- kdow n Collagen-degrading Proteinases – CD-40 L + + + Lipid core Libby P. Circulation 1995; 91: 2844 -2850. Fibrous cap IL-1 TNF- MCP-1 M-CSF Tissue Factor Procoagulant

Increased Expression of Interstitial Collagenase (CL) by Smooth Muscle Cells (SMC) and Macrophages (M ) in Human Atheroma Galis ZS et al. J Clin Invest 1994; 94: 2493 -2503.

Plaque Rupture with Thrombosis Thrombus 1 mm Illustration courtesy of Frederick J. Schoen, M. D. , Ph. D. Fibrous cap Lipid core

Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Syndromes, Results from: n Weakening of the fibrous cap n Thrombogenicity of the lipid core Illustration courtesy of Michael J. Davies, M. D.

CD 40 and Tissue Factor in Atheroma CD 40 Mach F et al. Circulation 1997; 96: 396 -399. Tissue Factor

CD 40 Ligation Induces Tissue Factor Expression in Human Monocyte-Derived Macrophages Cell Numbers 160 120 T cell/membranes/ -CD 40 L 160 120 T cell/ membranes 80 80 40 40 0 101 102 103 0 100 r. CD 40 L/ -CD 40 L r. CD 40 L 101 Log Fluorescence Mach F et al. Circulation 1997; 96: 396 -399. 102 103

CD 40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells Henn V et al. Nature 1998; 391: 591 -594.

Inflammation Can Promote Thrombosis Fibrinogen Via gp llb/llla Tissue Factor Platelet CD 40 L Fibrin Platelet Fibrinopeptides Platelet. Fibrin Thrombus

Inflammation Participates in All Phases of Atherothrombotic Disease n Lesion initiation n Lesion progression n Thrombotic complications

Thanks Slide Source: Lipids Online www. lipidsonline. org